TOWARD TRANSLATION OF NANFORMULATED PACLITAXEL-PLATINUM COMBINATION

纳米制剂紫杉醇-铂组合的转化

• 批准号: 10621403
• 负责人: ALEXANDER V KABANOV
• 金额: $ 11.79万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10621403
• 关键词: Address; Advanced Development; Animal Model; Animals; Anthracycline; Antigens; Biodistribution; Biological Assay; Breast Cancer Patient; CD2 gene; Carboplatin; Cisplatin; Clinic; Clinical; Clinical Data; Clinical Oncology; Combined Modality Therapy; Crossover Design; Data; Development; Disease; Dose; Drug Combinations; Drug Delivery Systems; Drug Kinetics; Excipients; Genetically Engineered Mouse; Goals; Human; Hydrophobicity; Immune; Immune checkpoint inhibitor; Immunotherapeutic agent; Immunotherapy; In complete remission; Investigational Therapies; Isogenic transplantation; Lead; Macaca mulatta; Malignant Neoplasms; Medical; Micelles; Modeling; Mus; Nanotechnology; Neoadjuvant Therapy; Neoplasm Metastasis; Paclitaxel; Pathologic; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Phase I/II Trial; Plasma; Platinum; Polymers; Positron-Emission Tomography; Postoperative Period; Pre-Clinical Model; Procedures; Prodrugs; Prognosis; Rattus; Recurrence; Reproducibility; Resources; Rodent; Safety; Sampling; Solubility; Study models; TP53 gene; Taxes; Technology; Testing; Therapeutic; Translations; Treatment outcome; Vertebral column; Visceral metastasis; Work; antitumor effect; base; cancer cell; cancer subtypes; chemotherapy; copolymer; drug development; good laboratory practice; human disease; improved; malignant breast neoplasm; mouse model; nanoformulation; nanoparticle; nanotherapeutic; nonhuman primate; novel; novel strategies; pre-clinical; programs; response; small molecule; standard of care; success; synergism; taxane; triple-negative invasive breast carcinoma; tumor; tumor microenvironment

TOWARD TRANSLATION OF NANFORMULATED PACLITAXEL-PLATINUM COMBINATION The goal of this proposal is to obtain pre-clinical data to enable the translation of a novel nanotechnology-based drug combination to treat triple negative breast cancer (TNBC). TNBC accounts for ∼10-20% of breast cancers and is associated with relatively poor prognosis, earlier disease recurrence and higher number of visceral metastases. Chemotherapy, in particular with anthracyclines and taxanes, remains the backbone medical management for both early and metastatic TNBC but a significant proportion of patients with early-stage TNBC unfortunately develop metastatic disease. Combination treatments using platinates and taxanes were shown to increase pathologic complete response rates in TNBC and improve survival in neoadjuvant treatment settings. We propose to use nanotechnology to improve the treatment of TNBC by co-delivering platinum and taxane drugs in the same nanoparticle to attack cancer cells in a synergistic fashion and produce greater antitumor effect. To address poor miscibility and drug loading of platinates and taxanes in many nanoparticles, we propose to use a high capacity polymeric micelles (PMs) of poly(2-oxazolne) (POx) block copolymers to incorporate drugs. In preliminary work we developed POXOL-CP PMs, a combination of PTX and hydrophobic cisplatin prodrug co-loaded in POx block copolymer micelles that has shown pharmacological synergy of solubilized drugs, better delivery of both drugs to tumors and improved efficacy in several animal models compared to the small molecule agents or their combination administered separately. The goal of this proposal is to obtain additional pre-GLP data for our new combination nanotherapeutic in rodent and non-human primate (NHP) models, develop validated assays and procedures for POXOL-CP PMs, further demonstrate its safety and efficacy and establish path for translation of POXOL-CP PMs to the clinic for TNBC patients. The project addresses the following aims: 1) Manufacture reproducible, stable, and safe POXOL-CP PMs, validate its safety and improved drug delivery to tumors in a mouse model of TNBC; 2) Demonstrate activity of POXOL-CP PMs compared to standard of care in Orthotopic Syngeneic Transplant (OST) and Genetically Engineered Mouse Models (GEMM) of TNBC that recapitulate the human disease. 3) Assess safety and PK profiles of POXOL-CP PMs in rat and NHP models. We will follow Good Experimental Practice (GEP) in data keeping and recording and develop Standard Operating Procedures (SOP) and follow guidance of a clinical and translational panel. If successful the results of this project will allow forming data package to support the Good Laboratory Practice (GLP) and Good Manufacturing Practice (GMP) work and compete for NCI Experimental Therapeutics (NExT) program, and/or other resources to advance development of POXOL-CP PMs on a path to the clinic to improve treatment outcomes for patients with TNBC.

向纳米形的紫杉醇 - 白斑组合翻译 该提案的目的是获得临床前数据，以使基于纳米技术的新型纳米技术翻译 治疗三重阴性乳腺癌（TNBC）的药物组合。 TNBC占乳腺癌的约10-20％ 并且与相对较差的预后，较早的疾病复发和较高的内脏有关 转移。化学疗法，尤其是蒽环类药物和紫杉烷，仍然是骨干医学 早期和转移性TNBC的管理 不幸的是发展转移性疾病。使用铂金和紫杉烷的组合治疗被证明 提高TNBC的病理完全反应率并提高新辅助治疗环境中的生存率。 我们建议使用纳米技术通过共同交付铂和紫杉烷来改善TNBC的处理 同一纳米颗粒中的药物以协同的方式攻击癌细胞并产生更大的抗肿瘤 影响。为了解决许多纳米颗粒中铂金酸盐和紫杉烷的不足性和药物加载，我们建议 使用高容量的聚合物胶束（PMS）poly（2-oxazolne）（POX）块共聚物合并 毒品。在初步工作中，我们开发了POXOL-CP PMS，PTX和疏水顺铂的组合 前药共同加载在痘痘块共聚物胶束中，该胶束已显示出可溶性的药物协同作用 与几种动物模型相比，药物，两种药物的递送更好 小分子剂或其组合分别给药。该提议的目的是获得 我们在啮齿动物和非人类灵长类动物（NHP）中新组合纳米治疗的其他前GLP数据 模型，开发了对内乐CP PMS的经过验证的测定和程序，进一步证明了其安全性和 疗效并为TNBC患者转换内乐-CP PMS的途径。项目 解决以下目的：1）生产可再现，稳定和安全的内乐-CP PMS，验证其安全性 并改善了TNBC小鼠模型中肿瘤的药物递送； 2）展示内乐-CP PMS的活性 与原位合元移植（OST）和基因工程小鼠的护理标准相比 TNBC的模型（GEMM）概括了人类疾病。 3）评估Poxol-CP的安全性和PK剖面 大鼠和NHP模型中的PMS。我们将在数据保存和记录中遵循良好的实验实践（GEP） 并制定标准操作程序（SOP），并遵循临床和翻译面板的指导。如果 成功的结果将允许成立数据包来支持良好的实验室实践 （GLP）和良好的制造实践（GMP）工作并竞争NCI实验治疗（下一项） 计划和/或其他资源，以促进通往诊所的途径改善内乐CP PMS的发展 TNBC患者的治疗结果。